Many kinds of parenteral drug therapy require continuous delivery in preference to single or multiple injections. Benefits that accrue from continuous therapy may include, for instance, reduction of toxic or other side effects associated with sharp pulses of drug, significant improvement in the effectiveness of the therapy, and increased patient comfort. The traditional manner of administering sustained parenteral treatments is via intravenous drip. Intravenous drip may be perfectly acceptable in a hospital environment, but it obviously imposes severe restrictions on the activity of the recipient. As a result, considerable research over the last few years has been devoted to the development of small portable infusion pumps. A range of infusion pump devices have appeared, including those with electric or clockwork motors that drive syringe or peristaltic pumps, and others powered by the elastic tension of an inflated balloon, or the vapor pressure of a volatile propellant. Literature incorporated herein by reference describing such pumps includes Controlled Release Micropump for Insulin Administration, (M. V. Sefton et al., Ann. Biomed. Eng., Vol. 7, pp. 329-343, 1979), Continuous Intravenous Arabinosyl Cytosine Infusions Delivered by a New Portable Infusion System, (J. Bottino et al., Cancer, Vol. 43, pp. 2197-2201, 1979), or product brochures from Auto-Syringe, Inc., Hooksett, N.H. and Cormed, Inc., Medina, N.Y. These infusion pump devices are typically strapped to the wearer, or carried on a belt or in a harness. Also, most infusion pump devices are designed to deliver relatively large quantities of fluid and do not dispense small volumes, of the order of a few milliliters or less, effectively.
An alternative approach that has been exploited to a limited extent is to drive the infuser osmotically, using a Rose-Nelson pump activated by imbibition of water or other driving fluid. The principle of the osmotic pump was originally conceived by Rose and Nelson in the 1950's. (S. Rose and J. F. Nelson, "A Continuous Long-Term Injector," Austral. J. Exp. Biol. 33, pp. 415-420 (1955)). A Rose-Nelson pump, typically, consists of three chambers: a salt chamber containing solid salt, a drug chamber, and a water chamber. The salt and water compartments are separated by a rigid membrane permeable to water but impermeable to salt; the salt and drug chambers are separated by a rubber diaphragm. In operation, water is imbibed osmotically into the salt chamber, causing the rubber diaphragm to expand into the drug chamber and forcing the drug out through the delivery orifice. Depending on the salt used, the osmotic pressure developed by this type of pump is usually between 50 and 200 atmospheres. The pressure required to pump the drug from the device is small in comparison, and hence the drug delivery rate remains constant as long as some excess undissolved salt remains in the salt chamber. In comparison with mechanically driven devices, Rose-Nelson pumps are small, reliable, and simple and cheap to manufacture. U.S. Pat. No. 3,604,417 discloses a modification of the Rose-Nelson pump in which a movable piston replaces the elastic diaphragm separating the drug and salt chamber, and both the drug and salt are loaded into the pump as solutions. U.S. Pat. No. 4,474,048 discloses another modification employing an impermeable elastic wall, and a movable end wall that can be screwed in to deliver a pulse dose of the contained drug at any time during the operation of the pump. U.S. Pat. No. 4,474,575 is a variant of 4,474,048 in which the flow rate of the dispensed agent can be varied by altering the area of semipermeable membrane exposed to the water chamber. U.S. Pat. No. 4,552,651 discloses a pump assembly for use with a small osmotic pump that can be filled in advance of use with the active agent to be dispensed. The action of the pump is initiated by filling the lower chamber of the housing with a hydrogel. Once the pump is in action, an optional mechanism for delivering pulse doses can be employed. All these osmotic pumps are self-driven and begin to operate as soon as they are primed with the contents of the several chambers.
U.S. Pat. No. 4,838,862, commonly owned with the present application and incorporated herein by reference in its entirety, describes a portable osmotic infusion pump that can be filled with the agent (typically a drug solution) to be dispensed, the osmotic salt and the driving fluid, and then stored as required. U.S. Pat. No. 4,898,582, also commonly owned with the present application and incorporated herein by reference in its entirety, describes a portable osmotic pump that includes a housing with two side-by-side compartments, where one compartment contains the osmotic pump, and the second compartment contains the driving liquid for the pump. The latter two patents describe osmotic pumps that can be filled with all required fluids, including the drugs to be delivered, stored until needed, and then activated very rapidly on demand. They are therefore excellent systems for use as disposable drug infusion devices.
Many limitations of these infusion pump devices, however, have not yet been addressed or resolved. One limitation of some of these infusion pump systems is that the patient does not have control over activation of the device, or has only limited control. For example, if a device is activated by ingestion, it will begin to release drug as soon as comes into contact with internal fluids. Another limitation is that, for many of these systems, the delivery rate of the infusate is not controlled.
Yet another limitation of some of these infusion pump devices are the problems accompanying long-term storage of the devices. Many substances such as drugs fare poorly when stored, particularly in solution, for a period of time in a delivery device, and particularly for periods of up to two years. The drug may change or deteriorate chemically and pharmacologically, and may precipitate out of solution. [The drug may also be degraded by interaction with other components of the system that diffuse into the drug chamber.] Other problems can occur if the drug solution comes into contact with other components of the device, such as elastic diaphragms, the materials lining the drug chamber, or infusion tubing and needle assemblies. Such designs create a number of storage, material stability, and material biocompatibility problems that are difficult to solve for many of the drug solutions that could conceivably be delivered. Yet another limitation of these devices is the difficulty associated with maintenance of device sterility during production and storage. These aspects are not adequately addressed in available disposable infusion devices and are problems that therefore limit their use.
One means for resolving the problems of maintaining device stability and sterility during long-term infusate storage, described in detail in the present disclosure, is to contain the infusate in a flexible pouch within the device. In one embodiment of the invention, the pouch could be a part of the device that is filled with the infusate during manufacturing, or later, for example by a pharmacist or other person, a short time before the device is used. There are several instances in the patent literature of infusion pumps where the liquid infusate is contained in a separate pouch within the device, for example, U.S. Pat. Nos. 4,191,181, 4,201,207, 4,398,908, and 4,525,164. After activation, these devices develop a pressure that is exerted on the pouch. These devices also typically incorporate a means of controlling the delivery rate of the infusate from the pouch. In many of these devices, however, this delivery rate is controlled by directly regulating the flow of the infusate out of the device, for example, by a flow-rate controlling valve. This configuration presents a number of problems. For example, both the initial sterilization and the maintenance of device sterility are difficult, due to the presence of small compartments and crevices in contact with the infusate that may be difficult for the sterilizing agent to reach. Another problem with direct flow regulation of the infusate fluid is that shear effects created, for example by fluid passing through a valve, may damage molecules in solution in the infusate, for example, proteins or other large molecules. A third problem is that these rate-controlling elements, valves, and the like are relatively unreliable.
One solution to the flow-control problem is to control the infusate delivery indirectly, for example, by controlling the pressure applied to the infusate pouch instead of infusate flow itself. U.S. Pat. No. 4,596,575 discloses a small implantable liquid infusion pump driven by a mechanical pump wherein device activation and flow rate are controlled by electronic regulation of the pump. This device is particularly intended for the delivery of insulin and contains two collapsible reservoirs in a rigid housing, one of which contains the infusate. The space between the outer wall of this reservoir and its rigid housing is filled with the drive liquid. The second reservoir is filled with the drive liquid, and the space between the outer wall of this reservoir and its rigid housing is maintained at subambient pressure. The drive liquid is pumped from the second reservoir into the outer space of the first housing to exert pressure on the first reservoir and thus deliver the liquid infusate. The electronic control unit controls two valves that restrict the flow rate of the drive liquid; thus the infusate does not come in contact with the valving system. This is a complex system, however, containing both mechanical and electrical parts, and is therefore prone to failure. The device is also provided with a separate refill system that may be used to refill the infusate reservoir. This type of refill mechanism presents sterility problems during longterm use, particularly because it is used in an implantable device that cannot be cleaned during use.
U.S. Pat. No. 4,034,756 discloses a small osmotic pump for use in an aqueous environment, such as the gastrointestinal tract, in which the liquid infusate (e.g. a drug) is contained in a flexible bag within the device, and the osmotic fluid exerts pressure directly on the flexible bag to effect liquid delivery. The flexible bag can be filled with the infusate during pump manufacture, or the bag can be filled with the infusate at a later time. This osmotic pump is simple, reliable, and sterilizable. Unfortunately, it can be activated only by exposure to an aqueous environment, and is therefore limited generally to internal use for drug delivery. The device is activated by ingestion or otherwise exposing the device to internal fluids, and rate control is solely a function of the permeability characteristics of the outer canister.
U.S. Pat. No. 4,193,398 describes a similar osmotic infusion pump that is portable and intended for extracorporeal use, i.e. the device is mounted externally. In the principle embodiment of this patent, the infusate is contained in a flexible polymeric bag made of polyvinyl chloride or some like material. An aqueous solution is contained in a second bag, while the osmotic solution is contained in a rigid chamber that encloses the infusate bag. In use, water diffuses through a semipermeable membrane separating the water bag from the osmotic solution chamber, and this water flow produces a pressure on the flexible infusate bag. In the normal mode of use, this device is loaded with the three fluids (the infusate, the osmotic solution, and water) immediately before activation, and then connected to the patient's infusion system. One problem with this embodiment of the device, however, is the sterility problems attendant with filling the device with fluids prior to use. Therefore, this embodiment is primarily suitable for a hospital setting. In another embodiment, a rupturable or removable water-impermeable barrier separates the semipermeable membrane from the osmotic solution. In principle, incorporation of such a barrier into the device would allow it to be loaded with the three fluids, stored for a prolonged period, and then activated when required. In fact, this embodiment would not be practical for several reasons. First, in this embodiment, the osmotic solution and infusate are separated by only a flexible polymeric bag for a period that could be as much as two years or more. (A typical pharmaceutical product has a shelf storage time of at least two years.) Since this is a medical device, complete integrity of the system is an absolute requirement, and contamination of the infusate is unacceptable. It is almost impossible to meet this requirement in the device described in 4,193,398, for diffusion of solutions across the barrier created by the bag material will occur on storage. Second, in this device, the membrane is exposed to water for the entire storage period of the device. Again, this is not tolerable. Semipermeable membrane materials, by their nature, must be made of hydrophilic polymers that are susceptible to slow degradation and hydrolysis by water. This is a well-known problem with the most widely used class of cellulose acetate semipermeable membranes. Thus the membrane, by being exposed to water for the full storage period, would degrade and lose its integrity. Therefore, incorporation of rupturable or removal barrier as an activation means is not useful where the device is meant to be stored for a prolonged period of months or years prior to use.
Each of these references describes a portable infusion pump that incorporates an infusate pouch or reservoir in a specific configuration, and usually with a specific motive force, yet all have problems that have inhibited their use. These include a high cost of manufacture, difficulties with sterilizing the infusate chamber and contents, difficulties in maintaining sterility of the device, and problems with stability of the devices after prolonged storage. As a result, there remains a need for a reliable disposable infusion pump that can be loaded with sterile liquid infusate, that can maintain sterility during prolonged storage, and that can then deliver the infusate following the required pattern of delivery of very low flow rates on demand.
The present invention describes a disposable osmotic infusion pump that is small, light, and convenient for patient use. The novel feature of the pump described in the present disclosure is the method used to package the infusate. In U.S. Pat. Nos. 4,838,862 and 4,898,582, the infusate is separated from the osmotic chamber by an elastic diaphragm that can expand into the chamber containing the infusate and force the infusate from the device. We have discovered that it is possible to incorporate the infusate in a sealed, flexible but not necessarily elastic, pouch that is placed inside the osmotic chamber. This device has a number of advantages, one of the most important being that the infusate pouch can be manufactured, loaded with infusate, sealed, and sterilized in a completely separate operation to the construction of the rest of the pump. This is a considerable production advantage. In addition, with this design, the pouch can be made of nonelastic materials, allowing construction from simple, biocompatible materials that are relatively impervious to invasion by environmental agents such as oxygen, or other components of the device.